Adipositas ist besonders in den Industrienationen ein zunehmendes gesellschaftliches und ökonomisches Problem. Dabei sind vor allem die kardiovaskulären und metabolischen Begleiterkrankungen von entscheidender Bedeutung. In den letzten Jahren konnte gezeigt werden, dass verschiedene Adipozyten- und Hepatozyten-sezernierte Proteine Mediatoren von Insulinresistenz und Dyslipidämie darstellen. Kürzlich wurde Angiopoietin-related growth factor (AGF) als ein neues, von der Leber produziertes Protein, das potentiell Insulinresistenz und Adipositas antagonisiert, vorgestellt. Im Mausmodell waren AGF-überexprimierende Tiere schlanker und insulinsensitiver verglichen zu Kontrolltieren. Zudem entwickelten AGF-knockout-Mäuse eine Adipositas, Insulinresistenz sowie eine Leber- und Skelettmuskelverfettung. Weiterhin fand sich in epidermalen Keratinozyten eine Hypervaskularisierung bei transgenen Mäusen mit AGF-Expression. Dies macht AGF möglicherweise zu einem Zielgen in der Behandlung moderner Zivilisationskrankheiten, wie z.B. dem Diabetes mellitus Typ 2 (DMT2). Bisherige Publikationen über AGF basieren zumeist auf Tiermodellen. Über die Regulation beim Menschen existieren dagegen bislang nur wenige Studien. In der vorliegenden Arbeit wurde AGF im Serum verschiedener Patientenpopulationen mit einem erhöhten kardiovaskulären Risikoprofil (Patienten mit chronischer Dialysepflicht, DMT2, Präeklampsie [PE]) mittels enzyme-linked immunosorbent assay quantifiziert und mit Kontrollpatienten verglichen. Die Ergebnisse zeigen, dass AGF bei Patienten mit DMT2 im Vergleich zu Nichtdiabetikern signifikant erhöht ist. Bei terminal-niereninsuffizienten Patienten dagegen fanden sich signifikant niedrigere AGF-Konzentrationen im Serum. Bei PE-Patientinnen waren signifikant höhere AGF-Spiegel nachweisbar verglichen zu gesunden schwangeren Kontrollen. Die vorgestellten Daten weisen darauf hin, dass erhöhte AGF-Spiegel bei DMT2 und PE eine physiologische Gegenregulation darstellen könnten, die der Insulinresistenz bei DMT2 bzw. antiangiogenetischen Faktoren bei PE entgegenwirkt. Alternativ wäre – ähnlich der Insulinresistenz – eine Resistenz von Patienten mit DMT2 bzw. PE gegen AGF möglich mit einer reflektorischen Erhöhung dieses Hepatozyten-exprimierten Faktors. Die genaue Rolle von AGF bei kardiovaskulären Risikopatienten muss in zukünftigen Arbeiten noch weiter aufgeklärt werden.

Background: One of the most prevalent diseases in the world, type 2 diabetes mellitus is rising every year. Self-care refers to controlling one's own illness to prevent future complications. The nurses' work is oriented on a person-centered approach to inform, promote, encourage, and support the patient to maintain good health in consideration of their circumstances. Aim: The aim of this literature study was to describe persons' experiences with self-care of type 2 diabetes mellitus.   Method: A literature study based on qualitative scientific articles which were retrieved from PubMed and CINAHL. A thematic analysis was used to analyze the articles. The study's objective was accomplished.  Results: The two main themes were identified. Experiences that affect self-care and Experiences of self-care’s impact on life.  Conclusion: Self-care is influenced by several factors such as knowledge, experience of support and control. The self-care and adaptation required for these affects the lives of people with type 2 Diabetes. Nurses have a key role in patients' self-care by helping people manage self-care. / Bakgrund: En av de vanligaste sjukdomarna i världen, typ 2 diabetes mellitus ökar varje år. Egenvård avser att kontrollera sin egen sjukdom för att förhindra framtida komplikationer. På grund av detta är sjuksköterskornas arbete inriktat på ett personcentrerat förhållningssätt för att informera, främja, uppmuntra och stödja patienten att bibehålla en god hälsa med hänsyn till sina omständigheter. Syfte: Syftet med denna litteraturstudie var att beskriva personers erfarenheter av egenvård av typ 2 diabetes mellitus. Metod: En litteraturstudie baserad på kvalitativa vetenskapliga artiklar som hämtats från PubMed och CINAHL. En tematisk analys användes för att analysera artiklarna. Studiens mål uppnåddes. Resultat: Två huvudteman identifierades. Erfarenheter som påverkar egenvården och erfarenheter av egenvårdens påverkan på livet. Slutsats: Egenvården påverkar flera faktorer såsom kunskap, erfarenhet av stöd och kontroll. Egenvården och anpassningen som krävs för dessa påverkar livet hos personer med typ 2 diabetes mellitus. Sjuksköterska har en nyckelroll i patienters egenvård genom att hjälpa personer att hantera egenvården.

Pharmacometric modelling is widely used in many aspects related to type 2 diabetes mellitus (T2DM), for instance in the anti-diabetes drug development, and in quantifying the disease progression of T2DM. The aim of this thesis were to improve the design of early phase anti-diabetes drug development studies with the focus on the power to identify mechanism of drug action (MoA), and to characterize and quantify the progression from prediabetes to overt diabetes, both the natural progression and the progression with diet and exercise interventions, using pharmacometrics modelling. The appropriateness of a study design depends on the MoAs of the anti-hyperglycaemic drug. Depending on if the focus is power to identify drug effect or accuracy and precision of drug effect, the best design will be different. Using insulin measurements on top of glucose has increase the power to identify a correct drug effect, distinguish a correct MoA from the incorrect, and to identify a secondary MoA in most cases. The accuracy and precision of drug parameter estimates, however, was not affected by insulin. A natural diabetes disease progression model was successfully added in a previously developed model to describe parameter changes of glucose and insulin regulation among impaired glucose tolerance (IGT) subjects, with the quantification of the lifestyle intervention. In this model, the assessment of multiple short-term provocations was combined to predict the long-term disease progression, and offers apart from the assessment of the onset of T2DM also the framework for how to perform similar analysis. Another previously published model was further developed to characterize the weight change in driving the changes in glucose homeostasis in subjects with IGT. This model includes the complex relationship between dropout from study and weight and glucose changes. This thesis has provided a first written guidance in designing a study for pharmacometrics analysis when characterizing drug effects, for early phase anti-diabetes drug development. The characterisation of the progression from prediabetes to overt diabetes using pharmacometrics modelling was successfully performed. Both the natural progression and the progression with diet and exercise interventions were quantified in this thesis.

胰島素自我注射是第二型糖尿病的重要治療方法。然而，許多病患的心因性胰島素抗拒（PIR）使他們拒絕胰島素治療，因而導致血糖控制不良。本研究目的即嘗試找出影響第二型糖尿病患者接受胰島素治療與否之可能因素。我們採用計畫行為理論（TPB）為基本架構，此理論主張「態度」、「主觀規範」、「覺知行為控制」三個變項可決定對某行為之意圖，而意圖可預測此行為之發生。此外，我們將情緒變項整合進TPB架構中以提昇預測力，包括「同時情緒」（對行為本身當下之心理或生理反應）與「預期情緒」（預期未來行為之後果成真時的情緒反應）。我們採自陳式問卷，橫斷研究設計，總計457位目前未使用胰島素之第二型糖尿病患者參與研究。階層迴歸分析結果，三個TPB變項（態度、主觀規範、覺知行為控制）均顯著預測胰島素治療之意圖，可解釋39.1%變異量；加入情緒變項後，整體模式解釋力提昇，可解釋43.2%意圖之變異量，「負向同時情緒」及「負向預期情緒」均為顯著預測因子。比較血糖控制較佳（HbA1C < 9%）與血糖控制較差（HbA1C ≧ 9%）兩組受試者，「負向同時情緒」是研究模型中唯一有顯著差異之變項。本研究結果顯示TPB可成功應用於解釋PIR，而情緒變項之影響亦不容小覷。 / Insulin injection is an important treatment in the care of type 2 diabetes mellitus. However, psychological insulin resistance (PIR) has long been an obstacle for many patients to achieve optimal glycemic control. The purpose of this research is to identify the influencing factors in decision-making process of type 2 diabetic patients whether or not to undergo insulin therapy. We adopted the theory of planned behavior (TPB) as our theoretical basis, which argues attitude, subjective norm and perceived behavior control (PBC) are determinants of behavioral intention, and intention is the precursor of behavior. Besides, we integrated extra emotion variables into TPB, which were anticipatory emotion (immediate psychological and physical responses toward the behavior itself) and anticipated emotion (affective responses expected to be experienced in the future when behavioral outcomes occur), to expanded the predictive power of research model. A cross-sectional questionnaire study design was employed, and a total of 457 currently not using insulin type 2 diabetic patients participated in this research. The hierarchical regression analysis revealed that all three TPB variables (attitude, subjective norm, PBC) significantly predict intention to use insulin, which account for 39.1% variance of intention. After the addition of emotional variables, the research model explains intention variance up to 43.2%, with negative anticipatory emotion and negative anticipated emotion being significant determinants. In the comparison of better glycemic-control (HbA1C < 9%) and worse glycemic-control (HbA1C ≧ 9%) participants, negative anticipatory emotion is the only variable in our research model significantly differs between both groups. The results of this research indicate not only TPB is a useful framework in realizing PIR, but also the impact of anticipatory and anticipated emotions cannot be overlooked.

NOVEL METABOLIC REGULATORS AND PROINFLAMMATORY FACTORS IN THE ETIOPATHOGENESIS OF TYPE 2 DIABETES MELLITUS AND OBESITY: THE INFLUENCE OF PHARMACOLOGICAL AND DIETARY INTERVENTIONS MUDr. Miloš Mráz Doctoral Thesis ABSTRACT (EN) Identifying novel factors involved in the etiopathogenesis of obesity, diabetes mellitus and their complications has become one of the primary scopes of metabolic research in the last years. The aim of the present study was to evaluate the role of recently discovered metabolic and inflammatory regulators including fibroblast growth factors 19 and 21 and chemotactic cytokines in the development of obesity and type 2 diabetes mellitus (DM2). A total number of 182 patients were included into the study. They were divided into 3 groups - patients with obesity but without type 2 diabetes mellitus, individuals with obesity and type 2 diabetes mellitus and healthy control normal-weight subjects. Selected interventions included 2 to 3 weeks of very-low-calorie diet (VLCD - energy content 2500 kJ/day), 3 months of administration of PPARα receptor agonist fenofibrate and acute hyperinsulinemia during hyperinsulinemic isoglycemic clamp. Our results indicate that the increase of circulating FGF-21 levels after VLCD and fenofibrate treatment could contribute to positive metabolic effects of these...

This thesis focuses on the effects of n-3 polyunsaturated fatty acids (n-3 PUFA) on development of non-alcoholic fatty liver disease (NAFLD) in experiment, on prevalence of this condition in patients with type 2 diabetes mellitus and metabolic syndrome and also on non-invasive diagnostics. The aim was to study the effect of n-3 PUFA on NAFLD development in an experimental model and based on analysis of a group of patients with type 2 diabetes and metabolic syndrome to assess the prevalence of this condition. Lastly we aimed to evaluate non-invasive diagnostic methods of liver fibrosis and NASH. We demonstrated beneficial effects of n-3 PUFA administration on NAFLD development in a C57/Bl6 mice high fat methionin-cholin defficient dietary model of NAFLD. n-3 PUFA administration led to biochemical improvement, decrease of lipid accumulation in the liver as well as improvement of histology. These effects are determined by complex modulation of lipid metabolism, mainly due to decrease in availability of fatty acids for triglyceride synthesis in the liver, changes of adipokine levels and amelioration of proinflammatory status in the liver. In a group of type 2 diabetics we found NAFLD prevalence of almost 80%, 14% of these patients had also signs of liver fibrosis or cirrhosis. Non-invasive methods...

Background: Modern health systems are increasingly faced with the challenge to provide effective, affordable and accessible health care for people with chronic conditions. As evidence on the specific unmet needs and their impact on health outcomes is limited, practical research is needed to tailor chronic care to individual needs of patients with diabetes. Qualitative approaches to describe professional and informal caregiving will support understanding the complexity of chronic care. Results are intended to provide practical recommendations to be used for systematic implementation of sustainable chronic care models. Method: A mixed method study was conducted. A standardised survey (n = 92) of experts in chronic care using mail responses to open-ended questions was conducted to analyse existing chronic care programs focusing on effective, problematic and missing components. An expert workshop (n = 22) of professionals and scientists of a European funded research project MANAGE CARE was used to define a limited number of unmet needs and priorities of elderly patients with type 2 diabetes mellitus and comorbidities. This list was validated and ranked using a multilingual online survey (n = 650). Participants of the online survey included patients, health care professionals and other stakeholders from 56 countries. Results: The survey indicated that current care models need to be improved in terms of financial support, case management and the consideration of social care. The expert workshop identified 150 patient needs which were summarised in 13 needs dimensions. The online survey of these pre-defined dimensions revealed that financial issues, education of both patients and professionals, availability of services as well as health promotion are the most important unmet needs for both patients and professionals. Conclusion: The study uncovered competing demands which are not limited to medical conditions. The findings emphasise that future care models need to focus stronger on individual patient needs and promote their active involvement in co-design and implementation. Future research is needed to develop new chronic care models providing evidence-based and practical implications for the regional care setting.

Un score de risque polygénique (SRP) a été mis au point pour permettre une prédiction précoce du risque de néphropathie chez les patients atteints de diabète de type-2 (DT2). Le but de cette étude était d’évaluer l’impact économique de l’implantation du SRP pour la prévention de la néphropathie chez les patients atteints du DT2, par rapport aux méthodes de dépistage habituelles au Canada. Tout d’abord, une revue systématique de la littérature a été effectuée pour examiner les évaluations économiques publiées sur le DT2 et la néphropathie. Les principales techniques de modélisation observées dans cette revue ont été utilisées pour réaliser une analyse coût-utilité à l’aide d’un modèle de Markov. Les états de santé du modèle étaient la pré-insuffisance rénale (pré-IR), l’IR et le décès. Les paramètres d’efficacité du modèle ont été basés sur les résultats de l’étude ADVANCE. Les analyses ont été menées selon une perspective du système de soins et une perspective sociétale. Sur un horizon temporel de la vie entière du patient, le SRP était une stratégie dominante par rapport aux méthodes de dépistage habituelles, selon les deux perspectives choisies. En effet, le SRP était moins coûteux et plus efficace en termes d’années de vie ajustée en fonction de la qualité, par rapport aux techniques de dépistage usuelles. Les analyses de sensibilité déterministe et probabiliste ont démontré que les résultats demeurent dominants dans la majorité des simulations. Cette évaluation économique démontre que l’adoption du SRP permettrait de réduire les coûts et d’améliorer la qualité de vie des patients. / The current screening method for diabetic nephropathy (DN) is based upon the detection of urinary albumin and the decline of estimated glomerular filtration rate, which occurs relatively late in the course of the disease. A polygenic risk score (PRS) was developed for early prediction of the risk for type 2 diabetes (T2D) patients who experience DN. The aim of this study was to assess the economic impact of the implementation of the PRS for the prevention of DN in T2D patients, compared to usual screening methods in Canada. First, a systematic literature review was conducted to examine all published economic evaluations in T2D and DN. The main trends in modelling technics obtained from this review were used to conduct a cost-utility analysis using a Markov model. Health states include pre-end-stage renal disease (Pre-ESRD), ESRD and death. Model efficacy parameters were based on prediction of outcome data by polygenic-risk testing of the ADVANCE trial. Analyses were conducted from Canadian healthcare and societal perspectives. Over a lifetime horizon, the PRS was a dominant strategy compared to usual screening methods, from both a healthcare system and societal perspective. In other words, the PRS was less expensive and more effective in terms of quality-adjusted life years compared to usual screening technics. Deterministic and probabilistic sensitivity analyses showed that results remained dominant in the majority of simulations. This economic evaluation demonstrates that the adoption of the PRS would not only be cost saving but would also help prevent ESRD and improve patients’ quality of life.

This thesis focuses on the effects of n-3 polyunsaturated fatty acids (n-3 PUFA) on development of non-alcoholic fatty liver disease (NAFLD) in experiment, on prevalence of this condition in patients with type 2 diabetes mellitus and metabolic syndrome and also on non-invasive diagnostics. The aim was to study the effect of n-3 PUFA on NAFLD development in an experimental model and based on analysis of a group of patients with type 2 diabetes and metabolic syndrome to assess the prevalence of this condition. Lastly we aimed to evaluate non-invasive diagnostic methods of liver fibrosis and NASH. We demonstrated beneficial effects of n-3 PUFA administration on NAFLD development in a C57/Bl6 mice high fat methionin-cholin defficient dietary model of NAFLD. n-3 PUFA administration led to biochemical improvement, decrease of lipid accumulation in the liver as well as improvement of histology. These effects are determined by complex modulation of lipid metabolism, mainly due to decrease in availability of fatty acids for triglyceride synthesis in the liver, changes of adipokine levels and amelioration of proinflammatory status in the liver. In a group of type 2 diabetics we found NAFLD prevalence of almost 80%, 14% of these patients had also signs of liver fibrosis or cirrhosis. Non-invasive methods...

NOVEL METABOLIC REGULATORS AND PROINFLAMMATORY FACTORS IN THE ETIOPATHOGENESIS OF TYPE 2 DIABETES MELLITUS AND OBESITY: THE INFLUENCE OF PHARMACOLOGICAL AND DIETARY INTERVENTIONS MUDr. Miloš Mráz Doctoral Thesis ABSTRACT (EN) Identifying novel factors involved in the etiopathogenesis of obesity, diabetes mellitus and their complications has become one of the primary scopes of metabolic research in the last years. The aim of the present study was to evaluate the role of recently discovered metabolic and inflammatory regulators including fibroblast growth factors 19 and 21 and chemotactic cytokines in the development of obesity and type 2 diabetes mellitus (DM2). A total number of 182 patients were included into the study. They were divided into 3 groups - patients with obesity but without type 2 diabetes mellitus, individuals with obesity and type 2 diabetes mellitus and healthy control normal-weight subjects. Selected interventions included 2 to 3 weeks of very-low-calorie diet (VLCD - energy content 2500 kJ/day), 3 months of administration of PPARα receptor agonist fenofibrate and acute hyperinsulinemia during hyperinsulinemic isoglycemic clamp. Our results indicate that the increase of circulating FGF-21 levels after VLCD and fenofibrate treatment could contribute to positive metabolic effects of these...